Process for the preparation of indigotindisulfonate sodium (indigo carmine)

ABSTRACT

This invention relates to an improved method for the preparation of highly or substantially pure Indigotindisulfonate sodium (1). It further relates to the novel crystalline form I of Indigotindisulfonate sodium (1) and the process for its preparation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/150,123, filed Jan. 15, 2021, which is a divisional of U.S. patentapplication Ser. No. 16/471,999, filed Jun. 20, 2019, which is aNational Stage application of International Patent Application No.PCT/IN2017/050615, filed on Dec. 23, 2017, which claims priority toIndian Patent Application No. 201641044154, filed on Dec. 23, 2016, eachof which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to an improved process for the preparationof Indigotindisulfonate sodium (1). It further relates to novelcrystalline form I of Indigotindisulfonate sodium (1) and process forits preparation.

BACKGROUND

Indigotindisulfonate sodium (1) is chemically referred to as disodium3,3′-dioxo-2,2′-bi-indolylidene-5,5′-disulfonate.

German patent DE201108, describes the synthesis of Indigotindisulfonatesodium by converting 3-(2-nitrophenyl)-2-oxopropanoic acid to(E)-[2,2′-biindolinylidene]-3,3′-dione followed by reaction withsulphuric acid to provide Indigotindisulfonate sodium (1). There is noinformation about the purity and yield of the product.

SUMMARY

One object of the invention is to provide purification process forpreparing substantially pure Indigotindisulfonate sodium having puritygreater than 99%, preferably greater than 99.5% and total impuritiesless than 1.0% and preferably less than 0.5%.

Yet other object of the invention is to provide an improved process forpreparing crystalline form I of Indigotindisulfonate sodium containing4-7% of moisture content.

Another object of the invention is to provide purification process toremove the process Impurities which include disodium3,3′-dioxo-[delta2,2′-biindoline]-5,7′-disulfonate of impurity A,monosodium 3,3′-dioxo-[delta 2,2′-biindoline]-5 sulfonate of impurity Band sodium 2,3-dioxoindoline-5-sulfonate of impurity C.

Another object of the invention is to provide a process for preparingsubstantially pure Indigotindisulfonate sodium (1) which is having totalimpurity level less than 1.0%; preferably less than 0.5% and impurity Alevel less than 0.15%, Impurity B level less than 0.15%, impurity Clevel less than 0.15% and any unknown impurity is controlled below0.10%.

Accordingly, it is an object of the present invention to provide animproved process for the preparation of Indigotindisulfonate sodium (1)

The present invention for the preparation of Indigotindisulfonate sodium(1) comprises of the following steps:

1) First step involves the conversion of 2-nitrobenzaldehyde of compound(2) to 2,2′-biindolylidene-3,3′-dione of compound (3) in the presence ofa base

2) The second step involves sulphonation of2,2′-biindolylidene-3,3′-dione of compound (3) to form3,3′-dioxo-[δ2,2′-biindoline]-5,5′-disulfonic acid in situ. Theintermediate so formed was diluted with a mixture of suitable protic andaprotic solvents and treated with a suitable sodium salt to yield crude(Indigotindisulfonate sodium 1),

3) The final step involves the purification of the obtainedIndigotindisulfonate sodium (1) to isolate a crystalline compound (1)

According to this invention, there is provided a simple procedure forthe purification of Indigotindisulfonate sodium (1) by avoidingdistillation and other techniques using high temperatures.

Indigotindisulfonate sodium (1) obtained in the above procedure ishaving purity greater than 99% (by HPLC) and is devoid of the reactionimpurities A, B and C, preferably greater than 99.5% and totalimpurities less than 1.0% and preferably less than 0.5%.

Another object of the invention is to provide Indigotindisulfonatesodium (1) with elemental purity i.e. lead level less than 0.5 ppm andArsenic level less than 1.5 ppm, preferably combination of lead andarsenic is less than 2 ppm.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 : illustrates the X-Ray powder diffraction pattern (XRPD) ofIndigotindisulfonate sodium (1)

FIG. 2 : illustrates the infrared (IR) spectrum of Indigotindisulfonatesodium (1)

FIG. 3 : illustrates the differential scanning calorimetry (DSC) ofIndigotindisulfonate sodium (1)

DETAILED DESCRIPTION

The present invention relates to an improved process for the preparationof Indigotindisulfonate sodium (1) in substantially pure form.

Another object of the invention relates to the process for thepreparation of substantially pure form of Indigotindisulfonate sodium(1) with purity greater than 99%, preferably greater than 99.5%.

The detailed process involves:

-   -   a) Treating 2-nitrobenzaldehyde of compound (2) with suitable        base to obtain 2,2′-biindolylidene-3,3′-dione of compound (3).        The unknown impurities observed in the reaction product at this        stage are optionally removed by purification.

-   -   b) Converting 2,2′-biindolylidene-3,3′-dion of compound (3) in        to Indigotindisulfonate sodium of compound (1) by treating with        sulphuric acid in the absence of solvent at temperature ranging        from 20 to 35° C. followed by treatment with suitable base. The        compound 1 is isolated by adjusting pH to not less than 13.

-   -   c) Purifying the crude Indigotindisulfonate sodium of        compound (1) obtained above by recrystallizing from suitable        solvents to provide pure Indigotindisulfonate sodium (1)

Wherein, in step a) suitable base is selected from the group comprisingsodium hydroxide, sodium carbonate, sodium bicarbonate or the like;solvent is selected from acetone, DM water or mixtures thereof. Forremoval of impurities solvents are selected from acetone, methanol andDimethylformamide or mixtures thereof.

In step b) sulphuric acid is used as the reagent; solvents used for thequenching of the reaction mass are methanol, methyl-t-butyl ether andethyl acetate.

In step c) Indigotindisulfonate sodium is further purified from thesolvents selected from group comprising alcohols like methanol, ethanol,isopropyl alcohol, n-butanol; water; acetonitrile; tetrahydrofuran;acetone; ethyl acetate; dichloromethane or mixtures thereof.

In one aspect, the present invention provides a purification process toproduce substantially pure Indigotindisulfonate sodium (1) devoid of thebelow impurities A, B and C by HPLC analysis.

The purification process comprises the following steps:

-   -   i) Suspending crude Indigotindisulfonate sodium obtained in        step-b in suitable solvents selected from a group comprising of        protic or aprotic solvents or the mixtures thereof.    -   ii) Heating the suspension to 60-65° C.    -   iii) Cooling the suspension to 20-25° C.    -   iv) Filtering the suspension and washing with a suitable protic        solvent at 20-25° C. to Isolate crystalline form I of        Indigotindisulfonate sodium (1)    -   v) Optionally repeating the above process with mixture of        solvents to increase the purity of Indigotindisulfonate sodium        (1)

Wherein the protic or aprotic solvents used in the above purificationprocess are selected from the group consisting of water, methanol,ethanol, isopropyl alcohol, n-butanol, acetonitrile, tetrahydrofuran,acetone, ethyl acetate, dichloromethane or mixtures thereof.

Most preferable solvents used in the above purification process wereselected from a group comprising of water, methanol and acetone ormixtures thereof; the ratio of solvent mixture preferably used rangedfrom (methanol 7:DM water 5:acetone 3) and (methanol 3.5:DM water2.5:acetone 1.5)

The present invention facilitates the easy removal of many undesiredImpurities and maintains the pH of the product between 3.0 to 6.5 byproviding high purity Indigotindisulfonate sodium (1).

Indigotindisulfonate sodium (1) obtained by the above purification ishaving moisture content 4-7% as measured by Karl Fischer analysis

Indigotindisulfonate sodium (1) obtained by the purification process ofthe present invention is substantially pure and has purity greater than99%, preferably greater than 99.5% and total impurities less than 1.0%and preferably less than 0.5%.

Indigotindisulfonate sodium (1) obtained by the purification process ofthe present invention is substantially pure and has purity greater than99%, preferably greater than 99.5% measured by HPLC and which comprisesLead less than 0.5 ppm and Arsenic less than 1.5 ppm, which formsanother object of the invention.

Indigotindisulfonate sodium (1) obtained by the purification process ofthe present invention is comprising total impurities less than 1.0% andpreferably less than 0.5%, measured by HPLC and combination of lead andArsenic metals less than 2 ppm.

In addition, Indigotindisulfonate sodium salt (1) synthesized accordingto the present invention is having metal impurities as shown in table-2and forms yet another object of the invention.

The crystalline form I of Indigotindisulfonate sodium (1) obtained afterpurification is characterized by the X-Ray powder diffraction (XRPD)pattern as shown in FIG. 1 and table 1, infrared (IR) spectrum as shownin FIG. 2 and the differential scanning calorimetry (DSC) as shown inFIG. 3

TABLE 1 X-Ray diffraction data of Indigotindisulfonate sodium (1) S. no2 Theta ° C. Relative intensity I/I₀ % 1. 5.801 46.5 2. 10.03 9.4 3.10.55 5.8 4. 11.67 100 5. 14.4 22.9 6. 15.37 55.7 7. 16.92 6.1 8. 17.6272.3 9. 18.33 5.3 10. 20.31 97.1 11. 20.97 19.2 12. 21.96 8.5 13. 23.078.5 14. 24.03 22.6 15. 24.72 25.1 16. 26.54 93.7 17. 27.16 23.6 18.27.62 8.6 19. 27.80 6.9 20. 28.65 28.5 21. 29.01 15.1 22. 29.66 7.3 23.30.87 54.6 24. 32.83 10 25. 33.06 14.2 26. 33.62 10.6 27. 35.39 12.8 28.37.99 11.6 29. 38.8 6.2 30. 40.97 18.7 31. 43.36 8.4 32. 43.77 5.9 33.46.93 6.9 34. 48.76 5.3 35. 48.99 5.8

TABLE 2 Elemental results of indigo ICH safety limit S. No. Elementcarmine (ppm) (ppm) 1. Cadmium 0.001 0.2 2. Mercury Not Detected 0.3 3.Cobalt 0.041 0.5 4. Vanadium 0.075 1 5. Nickel 2.038 5 6. Thallium NotDetected 0.8 7. Gold 0.000 10 8. Palladium 0.002 1 9. Iridium NotDetected 1 10. Osmium 0.001 1 11. Rhodium Not Detected 1 12. RutheniumNot Detected 1 13. Selenium Not Detected 8 14. Silver Not Detected 1 15.Platinum Not Detected 1 16. Lithium Not Detected 25 17. Antimony 0.001 918. Barium Not Detected 70 19. Molybdenum 0.454 150 20. Copper 0.101 3021. Tin Not Detected 60 22. Chromium 13.133  110

The following examples further illustrate the present invention, butshould not be construed in any way as to limit its scope.

EXAMPLES Example-1

Preparation of 2,2′-biindolylidene-3,3′-dione (Compound 3)

To a clean and dry RB flask, 1000 mL of acetone, 500 mL of DM water and100 g of 2-nitrobenzaldehyde were charged and cooled to 0-5° C. To this500 mL (1M) of aqueous sodium hydroxide solution was added at 0-5° C.and the reaction mass was stirred for 3-4 hrs at 25-30° C. Aftercompletion of the reaction, the reaction mass was filtered under vacuumand the solid obtained was washed with 500 mL of DM water and 200 mL ofmethanol. The intermediate 2,2′-biindolylidene-3,3′-dione (Compound 3)obtained in this contains more than 3% of unknown impurities.

Purification Process to Remove Unknown Impurities:

The obtained solid was heated in a mixture of 700 mL acetone and 300 mLmethanol for 4-5 hrs at 55-60° C. Then the reaction mixture was cooledto 25-30° C. and filtered under vacuum. The obtained solid was filteredand washed with a mixture of acetone and methanol (1:1). The solid washeated in a mixture of 700 mL of acetone and 300 mL of methanol for 4-5hrs at 55-60° C. Then the reaction mixture was cooled to 25-30° C. andfiltered the solid under vacuum.

The solid so obtained was stirred in 1000 mL of methanol for 1-2 hrs at25-30° C. and filtered under vacuum at 25-30° C. Further the solid waswashed with 100 mL of methanol and dried for 8-10 hrs at 60-65° C. Tothis, 10 volumes of dimethyl formamide was added and stirred for 1 hr at100-110° C. The mixture was then cooled to 50-55° C., filtered andwashed the solid with 2 volumes of methanol and 1 volume of acetone. Thesolid so obtained was dried under vacuum at 60-65° C.

Yield: 18-21%

Purity: 96% (HPLC)

Chromatographic Conditions:

Column: Inertsil ODS 3 V, 4.6 × 250 mm, 5μ Wavelength: 285 nm Flow Rate:1.0 mL/min Column Temp.: 25° C. Injection volume: 20 μL Run time: 55 minFlow mode: Gradient

Example-2

Preparation of Indigotindisulfonate Sodium (Crude Compound 1)

To a clean and dry round bottom flask, 1500 mL of sulphuric acid and 100g of 2,2-biindolylidene-3,3′-dione (Compound 3) were charged. Then thereaction mixture was stirred for 1 hr at 25-30° C. After completion ofreaction, the reaction mixture was quenched/diluted with pre-cooledmixture of methanol (54 volumes), methyl-t-butyl ether (34 volumes) andethyl acetate (2 volumes) solvents at 5-10° C. The reaction mixture wasstirred for 30 minutes and filtered under vacuum at 5-10° C., Theobtained solid was washed with 500 mL of chilled methanol and suck driedfor 2-3 hrs. 1000 mL of DM water was added to the solid and passedthrough micron filter, to the filtrate 1000 mL of methanol was chargedand cooled to 5-10° C. Then the pH of the solution was adjusted to notless than 13 using aqueous sodium hydroxide solution. The precipitatedsolid was filtered and washed with 500 mL of chilled methanol at 5-10°C. to obtain crude Indigotindisulfonate sodium of compound (1) (pH: NLT13)

Yield: 60%

Purity: 95-98%

Example-3

Purification of Indigotindisulfonate Sodium (Compound 1)

i) The crude Indigotindisulfonate sodium solid compound (1) obtained inexample 2 was taken in a round bottom flask and charged 7 volumes ofmethanol, 5 volumes of DM water (Demineralized water) and 3 volumes ofacetone. The reaction mixture was heated for 4-5 hrs at 60-65° C.,cooled and stirred for 1-2 hrs at 20-25° C. The obtained solid wasfiltered and washed with 1 volume of methanol then suck dried for 2-3hrs.

ii) Optionally, the solid obtained in step i) was heated in a mixture of3.5 volumes methanol, 2.5 volumes of DM water and 1.5 volumes of acetonefor 4-5 hrs at 60-65° C. Then the mixture was cooled to 20-25° C. andstirred for 1-2 hrs. The solid was filtered and washed with 1 volume ofmethanol then suck dried for 2-3 hrs.

iii) Again, the obtained solid in step ii), optionally was taken in amixture of 3 volumes of DM water and 1.5 volumes of methanol at 25-30°C. The reaction mixture was heated for 4-5 hrs at 60-65° C., cooled andstirred for 1-2 hrs at 20-25° C. The product was filtered and washedwith methanol then suck dried under vacuum for 1-2 hrs.

iv) Optionally, the solid obtained in step i), ii) or iii) was taken in1.5 volumes of DM water and stirred for 8-10 hrs at 25-30° C., to this0.5 volume of methanol was added and stirred for 1-2 hrs. Then the solidwas filtered and suck dried under vacuum for 1-2 hrs. Then the finalsolid was dried under vacuum at 65-70° C. until LOD complies.

(Yield: 28-32%, Purity by HPLC: 99.9%, Assay: 99%, pH: 3-6.5)

v) Optionally, the solid obtained in step i), ii) or iii) was dissolvedin 2 volumes of DM water at 25-30° C., and stirred for 8-10 hrs. 1volume of methanol was then added and stirred for 1-2 hrs at 20-25° C.The solid so formed was filtered and washed with 0.5 volume of methanoland dried for 10-12 hrs at 65-70° C. until LOD and pH complies. If theLOD and the pH is not in the limit, then the material was stirred in 3volumes of water and I volume of methanol for 1-2 hrs at 25-30° C. Thesolid so obtained was washed with methanol, dried under vacuum. (pH:3-6.5, LOD: NMT 5.0%)

Yield: 28-32%

Purity by HPLC: 99.9%

Assay: 99.0%

Arsenic: 0.01 ppm

Lead: 0.02 ppm

Chromatographic Conditions:

A High-Performance Liquid Chromatography equipped with UltravioletSpectrophotometer as detector and an auto sampler.

Column: Inertsil ODS 3 V (4.6 × 250 mm, 5μ) Wave length: 245 nm FlowRate: 1.0 mL/min Injection volume: 10 μL Run time: 60 min Columntemperature: Ambient Flow mode: Gradient Diluent: Water

While the present disclosure has been illustrated and described withrespect to a particular embodiment thereof, it should be appreciated bythose of ordinary skill in the art that various modifications to thisdisclosure may be made without departing from the spirit and scope ofthe present disclosure.

What is claimed is:
 1. Indigotindisulfonate sodium of formula (I) in acrystalline form having a purity greater than 99.0% by HPLC at 245 nm


2. The Indigotindisulfonate sodium of formula (I) of claim 1, whereinthe crystalline form is characterized by an X-ray powder diffraction(XRPD) pattern comprising peaks at 11.67, 20.31, and 26.54 degrees 2theta±0.2 degrees 2 theta.
 3. The Indigotindisulfonate sodium of formula(I) of claim 2, wherein the X-ray powder diffraction (XRPD) patternfurther comprises peaks at 5.80, 15.37, and 17.62 degrees 2 theta±0.2degrees 2 theta.
 4. The Indigotindisulfonate sodium of formula (I) ofclaim 3, wherein the X-ray powder diffraction (XRPD) pattern furthercomprises peaks at 14.4, 20.97, 24.03, 24.72, 27.16, 28.65, and 40.97degrees 2 theta±0.2 degrees 2 theta.
 5. The Indigotindisulfonate sodiumof formula (I) of claim 1, wherein the purity is greater than 99.5% byHPLC at 245 nm.
 6. The Indigotindisulfonate sodium of formula (I) ofclaim 1, wherein the purity is 99.9% by HPLC at 245 nm.
 7. TheIndigotindisulfonate sodium of formula (I) of claim 1, comprising lessthan 0.15% of impurity (A) by HPLC at 245 nm


8. The Indigotindisulfonate sodium of formula (I) of claim 1, comprisingless than 0.15% of impurity (B) by HPLC at 245 nm


9. The Indigotindisulfonate sodium of formula (I) of claim 1, comprisingless than 0.15% of impurity (C) by HPLC at 245 nm


10. The Indigotindisulfonate sodium of formula (I) of claim 1, whereinany unknown impurity is less than 0.10% by HPLC at 245 nm.
 11. TheIndigotindisulfonate sodium of formula (I) of claim 1, comprising lessthan 2 ppm of lead and arsenic combined.
 12. The Indigotindisulfonatesodium of formula (I) of claim 1, comprising less than 0.5 ppm of lead.13. The Indigotindisulfonate sodium of formula (I) of claim 1,comprising less than 1.5 ppm of arsenic.
 14. The Indigotindisulfonatesodium of formula (I) of claim 1, comprising from 4 to 7% of moisturecontent.
 15. The Indigotindisulfonate sodium of formula (I) of claim 1,obtained by a process comprising: suspending crude Indigotindisulfonatesodium in a protic or an aprotic solvent to obtain a suspension; heatingthe suspension to 60-65°0 C.; cooling the suspension to 20-25° C.; andfiltering the suspension and washing with methanol at 20-25° C. toisolate pure crystalline Indigotindisulfonate sodium.
 16. TheIndigotindisulfonate sodium of formula (I) of claim 15, wherein theprotic or aprotic solvent is selected from the group consisting ofwater, methanol, ethanol, isopropyl alcohol, n-butanol, acetonitrile,tetrahydrofuran, acetone, ethyl acetate, dichloromethane, and mixturesthereof.